tbuckley/cabot-search huggingface dataset:
Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy
Authors: Yun Liu, Yang Li, Yuxi Wang, Congcong Lin, Dan Zhang, Juncheng Chen, Liang Ouyang, Fengbo Wu, Jifa Zhang, Lei Chen
Journal: Journal of Hematology & Oncology (2022)

Abstract Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure–activity relationships and future directions.
Light-evoked dendritic spikes in sustained but not transient rabbit retinal ganglion cells
Authors: Arne Brombas, Xiangyu Zhou, Stephen R. Williams
Journal: Neuron (2022)

Dendritic computations have a central role in neuronal function, but it is unknown how cell-class heterogeneity of dendritic electrical excitability shapes physiologically engaged neuronal and circuit computations. To address this, we examined dendritic integration in closely related classes of retinal ganglion cells (GCs) using simultaneous somato-dendritic electrical recording techniques in a functionally intact circuit. Simultaneous recordings revealed sustained OFF-GCs generated powerful dendritic spikes in response to visual input that drove action potential firing. In contrast, the dendrites of transient OFF-GCs were passive and did not generate dendritic spikes. Dendritic spike generation allowed sustained, but not transient, OFF-GCs to signal into action potential output the local motion of visual stimuli to produce a continuous wave of action potential firing in adjacent cells as images moved across the retina. Conversely, this representation was highly fragmented in transient OFF-GCs. Thus, a heterogeneity of dendritic excitability defines the computations executed by classes of GCs.
Long-Term Morbidity and Mortality in Children After In Utero Exposure to Maternal Cancer
Authors: Iben K. Greiber, Jakob H. Viuff, Lone Storgaard, Mona A. Karlsen, Øjvind Lidegaard, Anders P. Mikkelsen, Lene Mellemkjær, Cristel S. Hjortshøj
Journal: Journal of Clinical Oncology (2022)

PURPOSE In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero. METHODS This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis. RESULTS Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy. CONCLUSION Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.
Learning agents that acquire representations of social groups
Authors: Joel Z. Leibo, Alexander Sasha Vezhnevets, Maria K. Eckstein, John P. Agapiou, Edgar A. Duéñez-Guzmán
Journal: Behavioral and Brain Sciences (2022)

Abstract Humans are learning agents that acquire social group representations from experience. Here, we discuss how to construct artificial agents capable of this feat. One approach, based on deep reinforcement learning, allows the necessary representations to self-organize. This minimizes the need for hand-engineering, improving robustness and scalability. It also enables “virtual neuroscience” research on the learned representations.
Societies and other kinds of social groups
Authors: Mark W. Moffett
Journal: Behavioral and Brain Sciences (2022)

Abstract People live in distinct groups, notably territory-holding societies, whose boundaries aren't neatly defined by the traits that Pietraszewski describes for his socially aligned groups (or SAGs), as I propose calling them, which occur both within and between our societies. Although studying SAGs could prove enlightening, societies are essential human groups that likely existed long before the complex SAGs of today.
Neuroscientific Evidence for Processing Without Awareness
Authors: Liad Mudrik, Leon Y. Deouell
Journal: Annual Review of Neuroscience (2022)

The extent to which we are affected by perceptual input of which we are unaware is widely debated. By measuring neural responses to sensory stimulation, neuroscientific data could complement behavioral results with valuable evidence. Here we review neuroscientific findings of processing of high-level information, as well as interactions with attention and memory. Although the results are mixed, we find initial support for processing object categories and words, possibly to the semantic level, as well as emotional expressions. Robust neural evidence for face individuation and integration of sentences or scenes is lacking. Attention affects the processing of stimuli that are not consciously perceived, and such stimuli may exogenously but not endogenously capture attention when relevant, and be maintained in memory over time. Sources of inconsistency in the literature include variability in control for awareness as well as individual differences, calling for future studies that adopt stricter measures of awareness and probe multiple processes within subjects.
An updated list of drugs suspected to be associated with immune thrombocytopenia based on the WHO pharmacovigilance database
Authors: Ségolène Fuentes, Basile Chrétien, Charles Dolladille, Joachim Alexandre, Anaël Dumont, Alexandre Nguyen, Hubert de Boysson, Stéphane Chèze, Gwénola Maigné, Achille Aouba, Samuel Deshayes
Journal: Blood (2022)
Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches
Authors: Stephanie Lazar, J. Michelle Kahlenberg
Journal: Annual Review of Medicine (2022)

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that can result in substantial morbidity and mortality. Diagnosis and treatment of SLE are clinical challenges. Patient presentation and response to therapy are heterogeneous because of the complex immune dysregulation that results in SLE disease pathogenesis. An intricate interplay between genetic risk and skewing of adaptive and innate immune system responses leads to overproduction of type I interferons and other cytokines, complement activation, immune-complex deposition, and ultimately inflammation and tissue damage. Here, we review the classification criteria as well as standard and emerging diagnostic tools available to identify patients with SLE. We then focus on medical management, including novel therapeutics, nonpharmacologic interventions, and comorbidity management.
Covid-19: FDA authorises pharmacists to prescribe Paxlovid
Authors: Janice Hopkins Tanne
Journal: BMJ (2022)

<h3>ABSTRACT</h3> <h3>Background</h3> NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. <h3>Methods</h3> The phase 2 component of our randomized, placebo-controlled, phase 1-2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late phase studies in younger (18-59 years) and older (60-84 years) participants and was based on immunogenicity and safety data through day 35 (14 days after the second dose). Participants were randomly assigned to receive either one or two intramuscular doses of 5-µg or 25-µg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. <h3>Results</h3> After randomization, approximately 250 participants each were assigned to one of four vaccine groups or placebo. Of these, approximately 45% were older participants. Reactogenicity was predominantly mild to moderate in severity and of short duration (median &lt;3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose, and occurred less frequently and was of lower intensity in older participants. The two-dose regimen of 5-µg NVX-CoV2373 induced robust geometric mean titer (GMT) IgG anti-spike protein (65,019 and 28,137 EU/mL) and wild-type virus neutralizing antibody (2201 and 981 titers) responses in younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in convalescent sera for both age groups. <h3>Conclusions</h3> The study confirmed that the two-dose regimen of 5-µg NVX-CoV2373 is highly immunogenic and well tolerated in both younger and older participants. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number: NCT04368988).
Benign SNPs in the Coding Region of <i>TP53</i>: Finding the Needles in a Haystack of Pathogenic Variants
Authors: Thierry Soussi
Journal: Cancer Research (2022)

Abstract With the recent explosion in high-throughput genotyping technology, the amount and quality of SNP data have increased exponentially, facilitating the discovery of multiple uncommon SNPs in the human population. To provide unified and centralized resources for the scientific community, several repositories have been developed that aggregate numerous population studies and serve widely as references to filter natural variants in genetic analyses. However, they are largely biased toward European populations. TP53 gene is the most frequently mutated gene in human cancer, and pathogenic germline TP53 variants are associated with several cancer susceptibility disorders such as Li–Fraumeni syndrome. For these reasons, it is essential that TP53 SNPs are rigorously evaluated to avoid misclassifications that could impair patient management. The recent discovery of numerous benign SNPs within the coding region of TP53 can be attributed to surveillance of both global repositories and population-specific databases, with the latter enabling the recognition of additional TP53 SNPs in Japanese, African, and Indian populations. This review summarizes the body of evidence behind the identification of 21 TP53 variants and the information defining them as bona fide SNPs. This illustrates the need to include populations of different ethnic origins in genetic studies and the substantial benefits that can be derived from the information.
Cell fate decisions, transcription factors and signaling during early retinal development
Authors: Raven Diacou, Prithviraj Nandigrami, Andras Fiser, Wei Liu, Ruth Ashery-Padan, Ales Cvekl
Journal: Progress in Retinal and Eye Research (2022)

The development of the vertebrate eyes is a complex process starting from anterior-posterior and dorso-ventral patterning of the anterior neural tube, resulting in the formation of the eye field. Symmetrical separation of the eye field at the anterior neural plate is followed by two symmetrical evaginations to generate a pair of optic vesicles. Next, reciprocal invagination of the optic vesicles with surface ectoderm-derived lens placodes generates double-layered optic cups. The inner and outer layers of the optic cups develop into the neural retina and retinal pigment epithelium (RPE), respectively. In vitro produced retinal tissues, called retinal organoids, are formed from human pluripotent stem cells, mimicking major steps of retinal differentiation in vivo. This review article summarizes recent progress in our understanding of early eye development, focusing on the formation the eye field, optic vesicles, and early optic cups. Recent single-cell transcriptomic studies are integrated with classical in vivo genetic and functional studies to uncover a range of cellular mechanisms underlying early eye development. The functions of signal transduction pathways and lineage-specific DNA-binding transcription factors are dissected to explain cell-specific regulatory mechanisms underlying cell fate determination during early eye development. The functions of homeodomain (HD) transcription factors Otx2, Pax6, Lhx2, Six3 and Six6, which are required for early eye development, are discussed in detail. Comprehensive understanding of the mechanisms of early eye development provides insight into the molecular and cellular basis of developmental ocular anomalies, such as optic cup coloboma. Lastly, modeling human development and inherited retinal diseases using stem cell-derived retinal organoids generates opportunities to discover novel therapies for retinal diseases.
Evaluation of Infection-Related Hospitalizations and Drug Prescriptions Among Sepsis Survivors in Germany
Authors: Carolin Fleischmann-Struzek, Bianka Ditscheid, Josephine Storch, Norman Rose, Melissa Spoden, Christiane S. Hartog, Antje Freytag
Journal: JAMA Network Open (2022)

This cohort study assesses infection-related hospitalizations and outpatient drug prescriptions among sepsis survivors in Germany and compares changes in hospitalization and prescription rates before and after sepsis occurrence.
Diagnosis and management of allergy and respiratory disorders in sport: An EAACI task force position paper
Authors: Oliver J. Price, Emil S. Walsted, Matteo Bonini, John D. Brannan, Valérie Bougault, Kai‐Håkon Carlsen, Mariana Couto, Pascale Kippelen, André Moreira, Helena Pite, Maia Rukhadze, James H. Hull
Journal: Allergy (2022)

Allergy and respiratory disorders are common in young athletic individuals. In the context of elite sport, it is essential to secure an accurate diagnosis in order to optimize health and performance. It is also important, however, to consider the potential impact or consequences of these disorders, in recreationally active individuals engaging in structured exercise and/or physical activity to maintain health and well-being across the lifespan. This EAACI Task Force was therefore established, to develop an up-to-date, research-informed position paper, detailing the optimal approach to the diagnosis and management of common exercise-related allergic and respiratory conditions. The recommendations are informed by a multidisciplinary panel of experts including allergists, pulmonologists, physiologists and sports physicians. The report is structured as a concise, practically focussed document, incorporating diagnostic and treatment algorithms, to provide a source of reference to aid clinical decision-making. Throughout, we signpost relevant learning resources to consolidate knowledge and understanding and conclude by highlighting future research priorities and unmet needs.
Factors shaping the global political priority of addressing elder abuse: a qualitative policy analysis
Authors: Christopher Mikton, Laura Campo-Tena, Yongjie Yon, Marie Beaulieu, Yusra Ribhi Shawar
Journal: The Lancet Healthy Longevity (2022)

Globally, 1 in 6 people aged 60 years and older experience elder abuse in the community annually, with potentially severe physical and mental health, financial, and social consequences. Yet, elder abuse remains a low global priority. We aimed to identify the factors accounting for the low global political priority of elder abuse.We systematically searched relevant peer-reviewed literature and organisational reports in multiple databases and interviewed 26 key informants in the field of elder abuse. We used policy frameworks developed by previous research into the determinants of the priority of global health issues, and a qualitative methodology to thematically analyse the literature and interviews through triangulation of the data.The main factors identified were related to the nature of the issue (the inherent complexity of elder abuse, pervasive ageism, insufficient awareness and doubts about prevalence estimates, and the intractability of the issue), the policy environment (the restricted ability in the field of elder abuse to capitalise on policy windows and processes), and the capabilities of the proponents of prevention of elder abuse (disagreements over the nature of the problem and solutions, challenges in individual and organisational leadership, and an absence of alliances with other issues).Around 25 years ago, elder abuse started to register on the global agenda. Since then, the global priority for prevention of elder abuse has barely increased. This study identifies several inter-related factors that account for the issue's low priority and opportunities for overcoming these challenges. Chief among these opportunities is the UN Decade of Healthy Ageing 2021-2030, a unique 10-year-long policy window to increase the political priority of the prevention of elder abuse.World Health Organization.
Effectiveness of vaccination mandates in improving uptake of COVID-19 vaccines in the USA
Authors: Michelle M Mello, Douglas J Opel, Regina M Benjamin, Timothy Callaghan, Renee DiResta, Jad A Elharake, Lisa C Flowers, Alison P Galvani, Daniel A Salmon, Jason L Schwartz, Noel T Brewer, Alison M Buttenheim, Richard M Carpiano, Chelsea Clinton, Peter J Hotez, Rekha Lakshmanan, Yvonne A Maldonado, Saad B Omer, Joshua M Sharfstein, Arthur Caplan
Journal: The Lancet (2022)
Immunoglobulin A antibody composition is sculpted to bind the self gut microbiome
Authors: Chao Yang, Alice Chen-Liaw, Matthew P. Spindler, Domenico Tortorella, Thomas M. Moran, Andrea Cerutti, Jeremiah J. Faith
Journal: Science Immunology (2022)

Despite being the most abundantly secreted immunoglobulin isotype, the pattern of reactivity of immunoglobulin A (IgA) antibodies toward each individual’s own gut commensal bacteria still remains elusive. By colonizing germ-free mice with defined commensal bacteria, we found that the binding specificity of bulk fecal and serum IgA toward resident gut bacteria resolves well at the species level and has modest strain-level specificity. IgA hybridomas generated from lamina propria B cells of gnotobiotic mice showed that most IgA clones recognized a single bacterial species, whereas a small portion displayed cross-reactivity. Orally administered hybridoma-produced IgAs still retained bacterial antigen binding capability, implying the potential for a new class of therapeutic antibodies. Species-specific IgAs had a range of strain specificities. Given the distinctive bacterial species and strain composition found in each individual’s gut, our findings suggest the IgA antibody repertoire is shaped uniquely to bind “self” gut bacteria.
Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment
Authors: Quan Gao, Jiao Feng, Wencheng Liu, Chengyong Wen, Yihan Wu, Qian Liao, Liang Zou, Xinbing Sui, Tian Xie, Jinming Zhang, Yichen Hu
Journal: Advanced Drug Delivery Reviews (2022)
Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8+ T Cells and Antitumor Immunity
Authors: Yingshi Chen, Shu-Mei Yan, Zeyu Pu, Jinzhu Feng, Likai Tan, Yuzhuang Li, Hongrong Hu, Wenjing Huang, Yingtong Lin, Zhilin Peng, Xin He, Feng Huang, Hui Zhang, Yiwen Zhang
Journal: Cancer Research (2022)

Abstract Tissue-resident memory CD8+ T (TRM) cells have been associated with robust protective antitumor immune responses and improved prognosis of patients with cancer. Therefore, therapeutic strategies that modulate either the production or activity of TRM cells could be effective for treating cancer. Using a high-throughput drug screen, we showed that the neurotransmitter dopamine drives differentiation of CD8+ T cells into CD103+ TRM cells. In murine syngeneic tumor xenograft models and clinical human colon cancer samples, DRD5 served as the major functional dopamine receptor on CD8+ T cells and positively correlated with TRM cell density. DRD5 deficiency led to a failure of CD8+ T cells to accumulate in tissues, resulting in impaired TRM cell formation, reduced effector function, and uncontrolled disease progression. Moreover, dopamine treatment promoted the antitumor activity of CD8+ T cells and suppressed colorectal cancer growth in immunocompentent mouse models, and ex vivo preconditioning with dopamine enhanced the in vivo efficacy of chimeric antigen receptor (CAR)-T cells. Finally, in a patient with colorectal cancer cohort, dopamine expression was positively associated with patient survival and CD8+ T-cell infiltration. These findings suggest that dopaminergic immunoregulation plays an important role in the differentiation of CD8+ cells into CD103+ TRM cells and thereby modulates TRM-elicited antitumor immunity in colorectal cancer. Significance: Identification of an immunostimulatory function of dopamine signaling by promoting tissue-resident memory T-cell differentiation and sustaining T-cell effector functions reveals potential therapeutic strategies and prognostic biomarkers for colorectal cancer.